Sex, sex steroids, and diabetic cardiomyopathy: making the case for experimental focus

Abstract

More than three decades ago, the Framingham study revealed that cardiovascular risk is elevated for all diabetics and that this jeopardy is substantially accentuated for women in particular. Numerous studies have subsequently documented worsened cardiac outcomes for women. Given that estrogen and insulin exert major regulatory effects through common intracellular signaling pathways prominent in maintenance of cardiomyocyte function, a sex-hormone:diabetic-disease interaction is plausible. Underlying aspects of female cardiovascular pathophysiology that exaggerate cardiovascular diabetic risk may be identified, including increased vulnerability to coronary microvascular disease, age-dependent impairment of insulin-sensitivity, and differential susceptibility to hyperglycemia. Since Framingham, considerable progress has been made in the development of experimental models of diabetic disease states, including a diversity of genetic rodent models. Ample evidence indicates that animal models of both type 1 and 2 diabetes variably recapitulate aspects of diabetic cardiomyopathy including diastolic and systolic dysfunction, and cardiac structural pathology including fibrosis, loss of compliance, and in some instances ventricular hypertrophy. Perplexingly, little of this work has explored the relevance and mechanisms of sexual dimorphism in diabetic cardiomyopathy. Only a small number of experimental studies have addressed this question, yet the prospects for gaining important mechanistic insights from further experimental enquiry are considerable. The case for experimental interrogation of sex differences, and of sex steroid influences in the aetiology of diabetic cardiomyopathy, is particularly compelling-providing incentive for future investigation with ultimate therapeutic potential.

Metabolic remodelling in diabetic cardiomyopathy

“…Female STZ-induced T1D animals developed diastolic and systolic dysfunction much earlier than their male counterparts, with earlier ventricular remodelling, including increased LV dilation and reduced ejection fraction 86 . These changes were associated with down regulation of pro-survival Pim-1, and upregulation of proapoptotic signalling caspases, microRNA-1, and microRNA-208a 86 (see ref 87 . for comprehensive review).…”

Chronic type 2 but not type 1 diabetes impairs myocardial ischaemic tolerance and preconditioning in C57Bl/6 mice

“…Secondly, we have assessed outcomes in male animals, and despite healthy female myocardium exhibiting superior I-R tolerance (Reichelt et al, 2009), females appear specifically sensitised to the cardiovascular impacts of diabetes (Reichelt et al, 2013), including greater mortality after infarction (Roffi et al, 2013). Few experimental studies contrast male and female responses, but Desrois et al report myocardial I-R tolerance is selectively impaired by diabetes in aging female but not male rats, an effect independent of phospho-AKT levels (Desrois et al, 2004).…”

“…Few experimental studies contrast male and female responses, but Desrois et al report myocardial I-R tolerance is selectively impaired by diabetes in aging female but not male rats, an effect independent of phospho-AKT levels (Desrois et al, 2004). Influences of sex on the cardiac and coronary impacts of T1D and T2D warrant focused study (Reichelt et al, 2013).…”

Angiotensin-(1–7) treatment mitigates right ventricular fibrosis as a distinctive feature of diabetic cardiomyopathy

“…One important cardiovascular insult in diabetic patients is the development of heart failure, which is due to ill-defined cardiomyopathy, even in the absence of arterial hypertension and coronary atherosclerosis (1,3,13,20). However, current diabetic therapies are not sufficient to completely prevent diabetes-induced end-organ damage even with normalized hyperglycemia.…”